Acquired immune deficiency syndrome, or AIDS, is a fatal disease which has reached epidemic proportions among certain high risk groups. Several features of AIDS make therapy extremely difficult. The main target of the AIDS virus, now known as HIV, or human immunodeficiency virus, is the T4 lymphocyte, a white blood cell that marshals the immune defenses. This depletion of T4 cells in AIDS causes a severe depression of the immune response, so that a compound which is to be effective against AIDS must modify virus effect without much help from host immunity. Furthermore, the virus also affects cells in the central nervous system, where it is protected by the blood-brain barrier from compounds that might otherwise be effective against the virus. In infecting its host, the HIV binds to specific cell-surface receptor molecules. The virus penetrates the cell cytoplasm and sheds its protein coat, thereby baring its genetic material, a single strand of RNA. A viral enzyme, reverse transcriptase, accompanies the RNA. The virus which is, a retrovirus, reverse transcribes the RNA into the DNA. Ultimately, some DNA copies of the HIV genome become integrated into the chromosomes of the host cell.
This integrated viral genome, known as a provirus, may remain latent until the host cell is stimulated, such as by another infection. The proviral DNA is then transcribed into mRNA, which directs the synthesis of viral proteins. The provirus also gives rise to other RNA copies that will serve as the genetic material of viral progeny. The proteins and the genomic RNA congregate at the cell membrane and assemble to form new HIV particles, which then break off from the cell. Two HIV genes, tat and trt/art, appear to control this burst of replication, which destroys the cell. These genes code for small proteins that boost the transcription of provital DNA and the synthesis of viral proteins.
Several compounds have been shown to reduce the activity of reverse transcriptase in vitro. The reverse transcription is the step that is essential to viral replication and irrelevant to host cells. It has been found that HIV replication is considerably slower in the presence of compounds such as suramin, antimoniotungstate, phosphonoformate, and a class of nucleoside analogues known as dideoxynucleosides.
Nucleoside analogues are a class of synthetic compounds that resemble the naturally occurring nucleosides, which are chemical precursors of DNA and RNA. A nucleoside comprises a single-or double-ring base linked to a five-carbon sugar molecule. An analogue differs from the naturally-occurring nucleoside in large or small features or the base of the sugar. An enzyme that normally acts on a nucleoside in the course of viral replication can also bind to the nucleoside analogue. Because the nucleoside and the analogue differ, however, binding to the analogue can incapacitate the enzyme, thereby disrupting a molecular process crucial to viral replication.
Of the synthetic nucleoside analogues, dideoxyadenosine (ddA), dideoxyinosine (ddI) and dideoxycytidine (ddC), have been found to have potent in vitro activity against the human immunodeficiency virus (HIV) which causes AIDS. Additionally, dideoxycytosine has been found effective in vivo in treating patients with AIDS, and dideoxyinosine and dideoxyadenosine are currently being tested in vivo in patients with AIDS. Because the activated form of dideoxynucleosides (5'-triphosphate) appears to inhibit the replication of the virus at the stage of reverse transcription of de novo infection of the virus, it is most likely that a drug of this type must be taken continuously if the therapeutic effect is to be maintained. Since daily treatment for a long period might ensue, oral drug administration is envisioned as the most practical route for a patient population numbering in the thousands.
Drugs administered orally are exposed to a pH range of 1 to 2 in the human stomach environment for approximately one hour. This could result in drug stability problems with ddA, since this compound undergoes acid-catalyzed hydrolysis of the glycosidic bond at a rate 40,000 times faster than adenosine. It was found that ddA has a t.sub. 1/2 of 35 seconds at pH 1.0 at 37.degree. C. (FIG. 3). Cleavage of this compound not only reduces its efficacy, but potential problems of toxicity may occur due to formation of excessive quantities of one of the cleavage products.